16

2. Structure & Function of Cellular Membranes2.1 Membrane Lipids

1. Three Major Classes of Lipids:

   • Phosphoglycerides (Phospholipids): Composed of a glycerol-3-phosphate backbone, two hydrophobic fatty acid tails, and a polar headgroup (e.g., phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine).

   • Sphingolipids: Built on a sphingosine backbone rather than glycerol. Examples include sphingomyelin (phosphosphingolipid) and glycosphingolipids (cerebrosides, gangliosides) which display sugars on the extracellular surface.

   • Sterols: Characterized by a rigid four-ring steroid structure with a short hydrocarbon tail and a single polar hydroxyl group ($\text{-OH}$). The predominant sterol in animal membranes is cholesterol.

2. Lipid Asymmetry:

   • Outer (Exoplasmic) Leaflet: Enriched in phosphatidylcholine, sphingomyelin, and glycolipids.

   • Inner (Cytosolic) Leaflet: Enriched in phosphatidylethanolamine, phosphatidylinositol, and negatively charged phosphatidylserine (exposure to the outer leaflet serves as a phagocytic "eat-me" signal during apoptosis).

   • Asymmetry Maintenance: Established and maintained by ATP-dependent translocases:

     • Flippases: Transport specific lipids (e.g., phosphatidylserine) from the outer to the inner leaflet.

     • Floppases: Transport lipids from the inner to the outer leaflet.

     • Scramblases: Calcium-activated, ATP-independent enzymes that facilitate bidirectional, non-specific lipid scrambling during membrane synthesis or apoptosis.

3. Role of Cholesterol:

   • Acts as a bidirectional bidirectional fluidity buffer:

     • At elevated temperatures, its rigid ring structure restricts excessive phospholipid fatty acyl chain movement, reducing membrane fluidity and permeability.

     • At lower temperatures, it prevents tight packing and crystallization of hydrocarbon chains, preventing phase transition to a rigid gel state.

2.2 Membrane Dynamics and Fluidity

• Fluid Mosaic Model: The lipid bilayer functions as a two-dimensional fluid matrix in which lipids and integral proteins diffuse laterally unless constrained.

• Modes of Lipid Mobility:

  • Lateral diffusion: Rapid movement within the plane of the leaflet ($\approx 10^7\text{ times per second}$).

  • Rotation and Flexion: Spinning around longitudinal axes and movement of hydrocarbon tails.

  • Transverse (flip-flop): Spontaneous crossing from one leaflet to the other, which is thermodynamically unfavorable and exceptionally slow without enzymatic catalysis.

• Factors Regulating Fluidity:

  • Fatty Acid Chain Length: Shorter chains exhibit fewer van der Waals interactions, increasing fluidity.

  • Saturation Degree: Cis-double bonds introduce kinks that prevent close packing, lowering the melting transition temperature ($T_m$) and increasing fluidity.

2.3 Membrane Proteins

1. Classes of Membrane Proteins:

   • Integral (Transmembrane) Proteins: Span the bilayer entirely via hydrophobic segments (typically $\alpha$-helices containing $\sim 20\text{ to }25\text{ hydrophobic amino acids}$ or $\beta$-barrels).

   • Peripheral Proteins: Indirectly attached to membrane surfaces via non-covalent interactions (electrostatic or hydrogen bonds) with integral proteins or lipid polar headgroups.

   • Lipid-Linked Proteins: Anchored covalently to membrane lipids via GPI (glycosylphosphatidylinositol) anchors (exoplasmic face), or via prenyl groups and fatty acyl chains (e.g., myristoylation, palmitoylation on the cytosolic face).

2. Protein Mobility:

   • Demonstrated empirically via FRAP (Fluorescence Recovery After Photobleaching) and cell fusion experiments (e.g., mouse-human heterokaryons).

3. Mechanisms Restricting Protein Mobility:

   • Direct anchoring to the underlying cortical cytoskeleton (e.g., spectrin-actin networks in erythrocytes).

   • Tethering to macromolecular complexes in the extracellular matrix (ECM).

   • Intercellular junctions (e.g., tight junctions forming molecular "fences" that maintain polarized epithelial domains: apical vs. basolateral).

   • Formation of large protein-protein self-aggregates or partitioning into specialized micro